The present invention relates to processes for the preparation of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethyl-amino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine which is useful as a therapeutic agent.
The compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl)-ethoxy)-4-(5-(dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S) -(4-fluorophenyl)-morpholine is a potent and selective substance P (or neurokinin-1) receptor antagonist. Substance P antagonists have potential for use in the treatment of inflammatory diseases, emesis, depresssion, anxiety, and other neuropsychiatric diseases, including bipolar disorder and schizophrenia.
U.S. Pat. No. 5,612,337 describes the preparation of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-4-(5-(dimethylamino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine which has the structure: ##STR1## by a four step process starting from 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)-ethoxy)-3-(S)-(4-fluorophen yl)morpholine. With reference to Example 12, Method A, of U.S. Pat. No. 5,612,337, the compound is prepared as follows: ##STR2##
With reference to Example 12, Method B, of U.S. Pat. No. 5,612,337, the compound is also prepared as follows: ##STR3##
These prior art processes render the synthesis of this compound problematic when attempted on anything other than a laboratory scale. Therefore, there is a need for the development of a process which is readily amenable to scale-up and capable of practical application to a manufacturing plant.